The proposed study addresses the National Institutes on Aging: Pilot Research Grant Program PAR-98-021, Number 8. DNA polymorphisms. The project is unrelated to the currently funded research areas of the P.I., but it is a collaborative effort by members of several departments at our institution. Members of the Department of Pathology discovered a novel neuro- degenerative disease in a large, local family. The familial occurrence, which spans several generations, is consistent with an autosomal dominant disorder. Four autopsy cases from two generations have been studied thus far. Clinical studies on various members of the family are ongoing on various members of the family, and over 60 DNA samples are available from affected and unaffected individuals. The investigation of the disorder was advanced after the neuronal inclusion bodies that are its distinguishing pathological feature were isolated and were found to be composed primarily of neuroserpin (a serine protease inhibitor expressed primarily in the CNS). The pattern of inheritance and the known occurrence of serpin polymorphism genetic variants/mutations lead to the hypothesis that a dysfunctional neuroserpin is the cause of this unique neurogenerative disorder. The hypothesis to be tested is that the dysfunctional neuroserpin molecules aggregate into inclusion bodies whose accumulation over time cause neuronal cell dysfunction and injury, either directly or indirectly. The proposed experiments are designed to test the hypothesis that the neuroserpin is a mutant protein by determining its amino acid composition of protein, by sequencing the cDNA generated by RT-PCR, and by analyzing the genomic DNA. For any mutation identified which cosegregates with the disease phenotype, a molecular probe will be designed to screen all members of the family, unrelated normal controls, and individuals with other neurological diseases. Additional evidence to confirm that the inclusion bodies contain neuroserpin aggregates will be obtained by immunocytochemistry using an antibody produced from the isolated protein. The proposed study is designed to advance our understanding of the role that extracellular proteolysis plays in normal and abnormal neuro- physiology. The long-range goals are: 1) to understand why the expression of the defective gene causes disease and dementia; 2) to investigate the possible role of neuroserpin variants in other neurological diseases; and 3) to design rational therapy to treat the affected individuals.